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Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Authors
  • Heemskerk, M. T.1
  • Korbee, C. J.1
  • Esselink, J. J.1
  • dos Santos, C. Carvalho1, 2
  • van Veen, S.1
  • Gordijn, I. F.1
  • Vrieling, F.1
  • Walburg, K. V.1
  • Engele, C. G.1
  • Dijkman, K.3
  • Wilson, L.1
  • Verreck, F. A. W.3
  • Ottenhoff, T. H. M.1
  • Haks, M. C.1
  • 1 Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands , Leiden (Netherlands)
  • 2 Instituto Butantan, São Paulo, Brazil , São Paulo (Brazil)
  • 3 Biomedical Primate Research Centre, Rijswijk, The Netherlands , Rijswijk (Netherlands)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Oct 04, 2021
Volume
11
Issue
1
Identifiers
DOI: 10.1038/s41598-021-98980-z
Source
Springer Nature
Disciplines
  • article
License
Green

Abstract

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

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